Effective clearance of aggregated ?-syn from the brain parenchyma is expected to reduce the development and progression of both sporadic and familial PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). It has been shown that ?-syn induces microglial activation via TLR2. However, until now, there is no specific inhibitor of TLR2. Knockdown of TLR2 may not be a feasible approach as it would wipe out both basal as well as induced TLR2 signaling pathways. Since TLR2 is known to function via Myd88, to target this induced TLR2 signaling from the therapeutic angle, we have designed a peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that selectively inhibits TLR2 signaling pathway including fibrillar ?-syn-mediated microglial activation. Therefore, here, we want to test a novel hypothesis that intranasal administration of wtTIDM peptide suppresses neuroinflammation (Specific aim I) and decreases ?-synucleinopathy (Specific aim II) in A53T transgenic mice via TLR2. A positive outcome of this cutting- edge R21 grant proposal will delineate if selective targeting of activated status of one component of the innate immune system (TLR2) by wtTIDM peptide reduces Lewy body pathology, highlighting the discovery of a prospective intranasal agent to reduce ?-synucleinopathy in PD, DLB and MSA. 1